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<p>I put department up there as Biomedical Engineering. The full title should be: School of Biomedical Engineering.</p> / <p>The work presented in this thesis was focused on the surface modification of biomaterials with combinations of polyethylene glycol (PEG) and bioactive molecules (protein anticoagulants) for improved blood compatibility. Since the fate of biomaterials in contact with blood depends significantly on plasma protein-surface interactions, the objective of this work was to reduce non-specific protein adsorption using PEG and to promote specific protein interactions that could inhibit clot formation using protein anticoagulants as modifiers.</p> <p>Two anticoagulant molecules were used in this work: hirudin, a specific inhibitor of thrombin and corn trypsin inhibitor (CTI), a specific inhibitor of clotting factor XIIa. Gold, used as a model substrate, was modified with PEG and anticoagulant molecules using two methods referred to as sequential and direct. In the sequential method PEG was first immobilized on the surface and then the bioactive molecule was attached (conjugated) to the PEG. In the direct method, a PEG-bioactive molecule conjugate was first formed and then immobilized on the surface. Surfaces were characterized by contact angle, ellipsometry and x-ray photoelectron spectroscopy (XPS). Uptake of the bioactive molecules was measured by radiolabeling. Biointeraction studies included plasma protein adsorption, bioactivity assays using chromogenic substrates and clotting time assays. For PEG-hirudin and PEG-CTI surfaces (both direct and sequential) the protein resistance was similar to that of the PEG-alone surfaces. Despite having a lower density of bioactive molecule (both hirudin and CTI), the sequential surfaces showed superior bioactivity compared to the direct ones.</p> <p>To determine the optimal ratio of free PEG and bioactive molecule-PEG conjugate on the surface (best combination of protein resistance and bioactivity), PEG-CTI was immobilized on gold substrate with varying ratio of conjugated to free PEG using both direct and sequential methods. As the ratio increased, protein resistance was maintained while specific interactions (bioactivity) increased. The optimal composition appeared to be where all PEG molecules are conjugated to a CTI molecule.</p> <p>In the final part of this project, PEG and CTI were immobilized on polyurethane as a material with applicability to medical device construction. A sequential method was developed for this substrate. Comparison of the PEG-CTI surface with PEG only or CTI only surfaces indicated that the combination of PEG-CTI was effective both in reducing non-specific protein adsorption and promoting the specific interactions of CTI with its target plasma protein, factor XIIa. In fact, the presence of PEG improved CTI interactions with FXIIa compared with CTI only surfaces. Thus, sequential attachment of PEG and CTI may be effective for modifying polyurethane surfaces used in blood-contacting medical devices.</p> / Doctor of Philosophy (PhD)

The overall aim of this thesis is to improve knowledge about the prevention of infectious and bleeding complications in patients with hematological malignancies, primarily in those with chronic lymphocytic leukemia (CLL) and myelodysplatic syndrome (MDS). Hypogammaglobulinemia, impaired production of immunoglobulins (Ig), is an established risk factor for infection, but the impact of IgG pure subclass deficiency (IgG subclass deficiency with adequate production of IgG, IgA, and IgM) has been debated. In a retrospective single institution study, we concluded that pure IgG subclass deficiency in CLL patients is rare and is not associated with an increased risk of infection. Hence, routine analysis of IgG subclasses in patients with CLL is not warranted. There is no consensus on recommending vaccination against Streptococcus pneumoniae to CLL patients mainly because comparative studies are lacking. In our randomized trial, the efficacy of a conjugated pneumococcal vaccine on immune response was superior or equal to a polysaccharide vaccine for all pneumococcal serotypes common for the two vaccines. A conjugate pneumococcal vaccine should therefore be included in vaccination programs for patients with CLL. Bronchoalveolar lavage (BAL) is a well-established invasive method to identify the cause of pulmonary infiltrates in immunocompromised patients. In a retrospective trial, we have studied the diagnostic yield of BAL in patients with hematological malignancies. We concluded that BAL is highly useful in either verifying or excluding some of the important respiratory tract infections affecting these patients, particularly invasive pulmonary aspergillosis (IPA) and Pneumocystis jirovecii pneumonia (PJP). However, standardized procedures for BAL sampling should be continually revised to avoid unnecessary microbiological tests. Thrombocytopenia, an adverse prognostic factor in patients with MDS, can be aggravated by azacitidine, first-line treatment for high-risk MDS. Eltrombopag, a thrombopoietin-receptor agonist (TPO-R), alleviates thrombocytopenia in patients with immune thrombocytopenic purpura (ITP). In a phase I clinical trial, we concluded that the combination of eltrombopag and azacitidine in high-risk MDS patients with thrombocytopenia is feasible and well tolerated in doses up to 200 mg eltrombopag daily.